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  • Gary Birnbaum, MD

Looking backward to capture the future

Serum Neurofilament Light Chain Levels in Patients

With Presymptomatic Multiple Sclerosis

Kjetil Bjornevik, MD, PhD; Kassandra L. Munger, ScD; Marianna Cortese,MD, PhD; Christian Barro, MD; Brian C. Healy; DavidW. Niebuhr, MD; Ann I. Scher, PhD; Jens Kuhle,MD, PhD; Alberto Ascherio,MD, DrPH

JAMA Neurol. doi:10.1001/jamaneurol.2019.3238

Published online September 13, 2019

The Bottom Line: The onset of MS is defined by the onset of clinical symptoms and signs. However, several recent studies suggest that changes may be occurring in the central nervous system of persons who develop MS up to 10 years prior to their first attack. This paper studied blood levels of proteins called neurofilament light chains (NfL) before and after persons developed MS. Neurofilament light chains are proteins found in nerve cells. They are released into the spinal fluid and blood when nerve cells die. This paper shows that neurofilament light chains are elevated in the blood of persons who subsequently develop clinical MS up to 10 years prior to their first attack. Thus, some form of brain injury is occurring silently many years before diagnosis. No one knows what triggers MS, and looking “backwards” at possible causes is fraught with possible error. The observations presented in this paper make it possible to consider screening persons that have a high risk for developing MS early in life for the presence of elevated neurofilament light chains. Detecting changes in levels of NfL may allow the identification of possible MS-related triggering events, possibly also allowing early treatment and prevention of disability.



Key Points:

1. Persons entering the military have blood drawn at entry and every two years thereafter until discharge. Serum samples are frozen and stored. This paper describes studies of the serum from 60 persons who developed MS following entry into the military. Military records and exams by neurologists confirmed the diagnosis of MS.

2. The researchers used a very sensitive test to measure serum concentrations of proteins called neurofilament light chains (NfL). NfL are present in nerve cells or neurons. When neurons become injured or die NfL are released into the spinal fluid and eventually also show up in the blood.

3. Two groups of persons that developed MS while in the military were studied. One study group consisted of thirty persons who had only one serum sample available one year or longer prior to onset of their MS, with another sample drawn within one year of onset of their illness. Another thirty persons were studied who had multiple serum samples drawn between 5 and 10 years before onset of their MS, with other samples 2-5 years before onset of their disease and again within one year after diagnosis. Control samples were obtained from healthy age, sex, and race/ethnicity matched military, with two control individuals chosen for comparison with each person with MS.

4. Serum NfL levels were elevated prior to onset of their illness in both groups of persons with MS compared to their controls. In the group with only one serum sample prior to onset of MS, NfL levels increased further after onset of the MS. In the second group, with multiple serum sample stored prior to onset of disease, levels were elevated up to 10 years prior to onset of MS, with increasing serum levels in samples obtained closer to the beginning of their MS. No similar findings were noted in the control individuals.

5. These data indicate that some level of central nervous system disease was present for years prior to the onset of clinical MS.

6. There are several limitations of this paper. Since samples were obtained form persons in the military, more than 75% of the persons studied were men, a large distortion from the general population of persons with MS where two-thirds are women. Serum levels of NfL increase with age, and data were not presented as to what is a “cut-off” for normal levels at the different ages of the study participants. In addition, risk factors for the development of MS, such as low vitamin D levels and exposure to Epstein-Barr virus were not available for analyses. Finally, elevated NfL levels are not specific for MS, being found in many other diseases of the central nervous system. Thus, while very unlikely in view of the results from controls, it is possible that persons with MS had other, unidentified disease of their central nervous systems contributing to the elevated NfL levels.

7. Despite the limitations noted above, the results from this study indicate that the MS disease process may begin many years before the onset of clinical symptoms, and that this process involves a degeneration of nerve cells. Triggers for this process are not known but studies of persons at risk for MS early in their lives may allow such triggers to be identified.


Several recent studies suggested that there is a prodromal period of altered health in persons with MS up to 10 years prior to clinical onset of their MS. Primarily these studies noted more health-related physician and hospital encounters than control individuals, and involved issues related to the nervous system, the musculoskeletal system, and urologic and psychiatric symptoms. While observations are important, they were all retrospective and don’t allow one to determine the trigger of the events that led to increased health provider contact. The above noted paper describes a biologically measurable parameter that is abnormally elevated many years prior to the onset of MS. These observations strongly support the idea that the triggers for MS may occur very early in life.

There are well-documented factors that may increase susceptibility for MS. These include low vitamin D levels, early exposure to the common virus that causes infectious mononucleosis, namely the Epstein-Barr Virus, childhood obesity, and a person’s genes. There also are persuasive data that an environmental exposure is necessary for the development of MS. The nature of that exposure is not known.

The data from the above paper may allow researchers to determine what such an exposure may be. Certain individuals are at a higher risk for developing MS. These include persons with a strong family history of MS, namely individuals whose parents have MS, persons with siblings with MS, both adult and juvenile in onset, and especially identical twins, one of whom has MS. With the proper research protocol and proper informed consent one could screen high risk individuals early in life, perhaps annually, and measure their serum neurofilament light chains prospectively. If a sudden rise in NfL levels was noted, any recent environmental events could be identified (infections, head injury, medications) and possible associations with the subsequent development of MS noted. If sufficient numbers of persons were studied, and information pooled, a pattern may be noted that could provide insight into events triggering the disease. Such information could be of great value in terms of disease prevention and subsequent treatment.


The abstract of this paper is available.